-DIETHYYL RATIOS DURING HALOTHANE-DIETHYL ETHER ANAESTHESIA

F. W. Cr~RVENKO,M.D., AND S. L. VANDEWATER, M.D. Q

H~tLOTI-n~NE AND DmTHYL ETHER form an azeotrope which has been in use as an inhalation anaesthetic since it was reported in 1958.1 An azeotrope may be simply defined as a constant-boillng-point mixture. are stable to fractional distillation but can be separated by extractive distillation~ and chromatogra- phy. The type of bonding of halothane and diethyl ether is probably of low energy and is either by dipole moments or bonds. 2 The stability of the azeotrope in the body has been questioned, since studies using infrared spec- trometry showed changing halothane-diethyl ether ratios in breath during anaesthesia with the azeotrope, suggesting that biological mechanisms may be in- volved in the breakdown of the azeotrope, a Changing halothane-diethyl ether ratios may imply changing flammability conditions ff "free" diethyl ether is present. Using three volumes per cent inspired concentration, blood concentrations of each component of the azeotrope have been predicted, 1 and based on the pre- dicted blood levels of diethyl ether, it has been suggested that anaesthesia with the azeotrope offers an advantage over anaesthesia with halothane alone. The present study is concerned with the determination of halothane--diethyl ether ratios during laboratory and clinical situations and the measurement of blood halothane and diethyl ether concentrations during azeotrope anaesthesia using gas chromatography.

METI-IOn Calibration studies The chromatographic conditions consisted of an F & ~ model 700 chromato- graph with a flame ionization detector, a 6 foot )< 1/8 inch O.D. copper column packed with Porapak Q 50/80 mesh, and a 1 millivolt Moseley recorder. The injection port temperature was 170 ~ C, oven temperature 130 ~ C, detector tem- perature 200 ~ C, and helium carrier gas flow rate was 50 ml per minute. Quan- titation of the area under the halothane and diethyl ether peaks was done by a disc integrator. Sample injections of 400 microlitres of azeotrope vapour were used. All samples were done in duplicate except in the clinical study on respired gas. The azeotrope was made using 66 parts halothane and 34 parts diethyl ether vol/vol. 4 Repeatability studies were done on azeotrope vapour emerging

*Department of Anaesthesiology,Queen's Universityat Kingston. ~Extractive distillation is defined as distillation in-the presence of a which is rela- tively non-volatile compared to the components to be separated, and which is selected to enhance the relative of the components. 70 Canad. Anaesth. Soe. J., vol. 17, no. 1, January 1970 CERVENKO & VANDEWATER: HALOTHANE-DIETHYL ETHER RATIOS 71 from a Fluotec vaporizer with a carrier gas flow of three litres of and three litres of per minute. The halothane-diethyl ether ratios were deter- mined in five lots of azeotrope made on five different days and over a storage period of 9.5 days at room temperature.

Laboratory studies Circle absorber study. To determine the effect of soda lime, carbon dioxide, and water vapour on azeotrope, the following study was done in quadruplicate. Azeotrope vapour from a Fluotec vaporizer was introduced into a closed circle with the absorber off, using equal parts oxygen and nitrous oxide and an addi- tional reservoir bag at the face piece end until both reservoir bags were nearly full. The gas was circulated by alternate squeezing of the reservoir bags. After ten minutes, 400 mierolitres of gas from the inspiratory side were sampled and injected into the chromatograph. A Boyle Mark IH absorber canister containing fresh soda lime was added to the circuit, and the gas was circulated for ten minutes and again sampled. One hundred per cent carbon dioxide was intro- duced into the circle continuously for three to five minutes and circulated until the absorber became warm. The system was again sampled. The experiment was repeated with 250 ml of water added to the soda lime canister, and the carbon dioxide, soda lime, and water vapour from the canister introduced simultaneously. In vitro blood and water study. Samples of 10 ml heparinized whole blood were added to 38.5 ml capacity vials sealed with a rubber stopper and weighed. Azeotrope was injected through the stopper and the vial reweighed and mixed. After equilibration in a water bath at 20 ~ C, 25 ~ C, and 37 ~ C • 1.5 ~ C the halothane-diethyl ether ratio was determined by sampling 400 microlitres of the gas phase and injecting them into the chromatograph. This was repeated using 10 ml samples of water equilibrated at 21 ~ C, 25 ~ C, and 37 ~ C. Clinical study. Six premedicated patients undergoing elective minor urologic or plastic surgical procedures were induced with intravenous thiopental or diaze- pare and given halothane--diethyl ether azeotrope from the same Fluotec vapori- zer. Three patients were anaesthetized using a Fluotee vaporizer outside a circle absorber system with the vaporizer set up to 2.5 during induction and 0.75 to 1.5 for maintenance and with carrier of 3 litres of oxygen and 3 litres of nitrous oxide per minute. Respirations were spontaneous. Gas samples were taken at intervals for chromatographic analysis from the inspiratory and expiratory sides of the corrugated tubing. After inhalation anaesthesia had been established for 13 to 15 minutes, simultaneously 10 ml heparinized radial artery and peri- pheral venous blood samples were taken anaerobically for detelznination of halo- thane and diethyl ether concentrations. Arterial and venous blood samples were taken from an additional patient anaesthetized with azeotrope for 38 minutes. End expiratory gas samples were taken three to five minutes following cessation of anaesthesia. Three patients were anaesthetized with azeotrope using a non-rebreathing circuit with a flow of 4 litres of oxygen and 4 litres of nitrous oxide per minute. End expiratory breath samples were taken at intervals during anaesthesia, with 72 CANADIAN ANAESTHETISTS'SOCIETY JOURNAL spontaneous respiration and following cessation of anaesthesia for chromato- graphic analysis. In three patients end expired halothane and diethyl ether were quantitated during recovery from azeotrope anaesthesia. It was assumed that at a Fluotec setting of 1.0 and 8 litres of gas passing through the vaporizer, two-thirds volume per cent halothane and one-third volume per cent diethyl ether emerged. 4 The integrated areas of the halothane and diethyl ether chromatographic peaks from this Fluotec setting were used to determine the expired breath concentrations. Blood halothane and diethyl ether concentrations were determined by blood- air equilibration. 5 A calibration curve for halothane and diethyl ether was made by placing 10 ml samples of heparinized whole blood into three 36.5 rnl rubber stoppered vials, weighing, injecting three different halothane and diethyl ether eoneentrations, and reweighing. The vials were mixed and equilibrated in a water bath at 22 ~ C for thirty minutes. Four hundred microlitre samples of the gas phase in the vials were injected into the chromatograph and the calibration curve constructed. Blood samples from the anaesthetized patients were similarly equilibrated at 22 ~ C, and the blood concentration determined from the calibration curve.

OBSERVATIONS AND DISCUSSION Calibration Figure i is a sample ehromatogram of halothane--diethyl ether azeotrope. Elution times were eighteen seconds for water vapour, 100 seconds for diethyl ether, and 155 seconds for halothane. The mean halothane-diethyl ether vapour ratio of five lots of azeotrope was found to be 1.65 ___ 0.03 (st.) and the ratio was unaltered throughout all Fluotec settings of 0.5 to 4.0. The halothane--diethyl ether ratio of azeotrope changed little when determined on ten different days over a period of twenty-five days with a mean ratio of 1.60 ___ 0.01 (sE). Injec- tion repeatability of ten consecutive gas samples of azeotrope at a 1 per cent Fluotec setting with 3 litres of oxygen and 3 litres of nitrous oxide per minute resulted in a mean integrated area of 1,610 ___ 11 (SE) for diethyl ether and 2,753 • 38 (SE) for halothane.

Laboratory studies Figure 2 shows the results of the circle absorber experiment. The mean halo- thane-diethyl ether ratios following contact with soda lime, soda lime and carbon dioxide, and soda lime, carbon dioxide, and water vapour are statistically sig- nificantly different (p < 0.01) from that of azeotrope. The mean ratios after contact with carbon dioxide and carbon dioxide with water vapottr were not statistically different from the ratio after contact with soda lime alone (p > 0.05). Thus, soda lime can break down the azeotrope. Since the ratio increased, halothane is present in a proportionately greater quantity in the gas phase. Soda lime is known to adsorb inhalation anaesthetics, and the results suggest that diethyl ether is adsorbed onto soda lime in proportionately greater quantity than halothane. CERVENKO & VANDEWATER: HALOTHANE-DIETHYLETHER RATIOS 73

FmtraE 1. Chrornatogram of diethyl ether (1) and halothane (2).

In vitro blood and water study. Table I lists the altered halothane--diethyl ether ratio of azeotrope after the addition of different concentrations to blood and water, and the effect of temperature on the ratio. Since the ratio increased, proportionately more halothane is present in the gas phase. The change in ratio with temperature and concentration of azeotrope in both blood and water is com- patible with the fact that halothane and diethyl ether have different slopes of their blood/gas and water/gas partition coefficients at different temperatures. There is a marked difference in halothane--diethyl ether ratios in blood compared to water, with more halothane being present in the gas phase above water. This is explain- able by the fact that the blood/gas for halothane at 37 ~ C is 2.3 and the water/gas coefficient 0.74, signifying that halothane is more soluble in blood than in water. In contrast, at 37 ~ C diethyl ether has a blood/gas parti- tion coefficient of 12.1 and a water/gas coefficient of 13.1, signifying greater in water than in blood. It is postulated that the change in halothane and diethyl ether ratio in blood and water occurs by extractive distillation. The solvent in this case has a 50 to 100 ~ C higher than the azeotrope. ~ 74 CANADIAN ANAESTHETISTS' SOCIETY ~OUHNAL

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Fmtms 2. Mean halotbane-diethyl ether ratios in the circle absorber study (see text). The bars indicate the standard error of the mean. Therefore, water probably acts as the solvent for the extractive distillation of halothane-diethyl ether azeotrope. Clinical studies. The changes in halothane--diethyl ether ratios in the respired gases of patients anaesthetized with azeotrope are showal in Figure 3 where the circle absorber system was used and Figure 4 where a non-rebreathing system was used. The results show that the body breaks down halothane-diethyl ether azeotrope. Since the ratio changes are greater in end expired breath of the non-rebreathing system, it is probable that soda lime played little role in azeotrope breakdown in the circle system; this is especially likely when one considers the continued inflow of fresh azeotrope, nitrous oxide, and oxygen to the circle system to "dilute" the expired ratio change. The results are in general agreement with those

TABLE I HALOTHANE-DIETHYL ETHER RATIOS IN BLOOD AND

Temperature (~ Azeotrope added (mg %) 20 21 25 37 Blood 5.0 6.95 5.73 3.52 12.9 5.99 5.22 3.52 23.9 5.33 4.51 2.87 Water 6.6 16.40 12.64 7.18 15.6 10.10 8.29 4.56 CERVENKO & VANDEWATEIq: HALOTHANE-DIETHYL ETHER RATIOS 75

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Anaesthesia Time (min.) l Off F~c~.w~ 3, Mean halothane--diethyl ether ratios in the inspired and expired sides of a circle system in patients anaesthetized with azeotrope and following cessation of anaesthesia. The bars indicate the range o{ ratio change. reported except that it is postulated that the breakdown of halothane-diethyl ether azeotrope is by the physio-chemical method of extractive distillation and not by biological mechanisms.8 There was a predominance of halothane in the expired breath during the period of study. This implies that proportionately more diethyl ether was being taken up by the body. End expired samples taken in four of the six patients during recovery from anaesthesia showed a halothane- diethyl ether ratio lower than that of the azeotrope and therefore a greater quantity of diethyl ether present than in the azeotrope. In the three patients in whom end expired gases were quantitated, the patient who showed the lowest ratio had 0.04 volumes per cent halothane and 0.03 volumes per cent diethyl ether present. The azeotrope re-forms in expired breath, ~ and this would leave little free diethyl ether - well below the minimum ~tammability of 2 volumes per cent3 Table II lists the arterial and peripheral venous blood concentrations of halo- thane and diethyl ether after thirteen to fifteen minutes of nitrous oxide and azeotrope anaesthesia. The additional patient studied after 38 minutes of azeo- trope anaesthesia had an arterial blood concentration of 2.8 mg per cent diethyl ether and 6.0 mg per cent halothane, and peripheral venous blood concentration of 2.1 per cent diethyl ether and 5.0 mg per cent halothane. The halothane con- centrations were consistent with light halothane anaesthesia. The arterial blood diethyl ether concentrations were lower than predicted1 and well below the 17 to 62 mg per cent reported for ether analgesia3 The diethyl ether arterial blood 76 CANADIAN ANAESTHETISTS'SOCIETY JOURNAL

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lb is 2'0 ~ lb l's Anaesthesia Time (min) l Off Fmul~ 4. Mean halothane-diethyl ether ratios in end expired gas in patients anaesthetized with azeotrope using a non-rebreathing system, and following cessation of anaesthesia. The bars indicate the range of ratio change. concentration range of 17 to 62 mg per cent was achieved after an induction of anaesthesia using high inspired concentrations to Guedel's stage ~ti, plane 1 depth of anaesthesia, and then lightening the patient to Artusio's stage I plane 3 depth, which was maintained with 0.7 to 1.7 volume per cent inspired diethyl ether. The arterial blood diethyl ether concentrations in the present study are consistent with the fact that maximal inspired concentration of diethyl ether during induction was approximately 0.8 volumes per cent (Fluotec set at 2.5) and the maintenance concentrations 0.25 to 0.5 volumes per cent (Fluotec set at 0.75 to 1.5). TABLE II BLOOD CONCENTRATIONS (mg %) AFTER 13-15 MINUTES OF AZEOTROPE ANAESTHESIA

Arterial Venous Patient dlethyl ether halothane diethyl ether halothane 1 2.2 7.6 1.8 5.0 2 1.9 4.8 1.0 3.2 3 1.6 4.7 1.4 3.9 Mean 1.9 5.7 1.4 4.0

S UNL'vIAltY The bond(s) which join halothane-diethyl ether azeotrope can be broken by gas chromatography, soda lime, water, and blood, in vitro and in the body. CERVENKO & VANDEWATER: I-LALOTHANE-DIE'IZHYLETHER RATIOS 77 Soda lime breaks the bonding probably in a manner similar to that in gas chro- matography. It is postulated that water, blood, and the body break the bonding by extractive distillation. Halothane-diethyl ether ratios in expired breath during azeotrope anaesthesia increased, indicating a greater proportional uptake of diethyl ether by the body; and the ratio tended to decrease during recovery, indicating a greater proportional elimination of diethyl ether. During recovery from azeotrope anaesthesia, expired diethyl ether concentrations were below the minimum even without taking into consideration reformation of azeotrope in expired breath, which in itself would decrease the likelihood of flammability. Arterial and venous blood concentrations of halothane and diethyl ether during light azeotrope anaesthesia were determined. The diethyl ether blood concentrations are well below those reported for diethyl ether analgesia.

I~M~ Les liens qui unissent l'halothane-dirthyl 6ther azrotropique peuvent &re brisrs par chromatographie gazeuse, per la chaux sodre, l'eau et le sang in vitro et in vivo. La chaux sodre brise la liaison probablement de la mSme mani~re que la chromatographie gazeuse. On admet clue l'eau, le sang et l'organisme brisent la liaison par distillation d'extraction. Le rapport halothane--dirthyl 6ther augmentait dans l'air expir6 durant l'anesthfisie au mrlange az~otropique, ee qui indiquait une plus grande absorption de dirthyl 6ther par l'organisme; par contre le rapport tendait ~t diminuer durant le r6veil, ee qui indiquait une plus grande 61imination proportionnelle de dirthyl 6ther. Durant le rrveil de ranes- thrsie au mrlange azrotropique, les concentrations de di6thyl 6ther expir~ 6talent au-dessous de la limite infrrieure d'inflammabilitr, mSme sans tenir eompte de la reformation, dans l'air expirr, de mrlange azrotropique qui en soi diminuerait la possibilit6 d'inflammabilitr. On a drtermin6 les concentrations dans le sang artrriel et dans le sang veineux d'halothane et de dirthyl &her durant l'anaesth6sie 16g~re au mrlange azrotropique. Les concentrations de dirthyl 6ther dans le sang sont sensiblement inf~rieures ~ celles qu'on rapporte pour l'anesthrsie au dirthyl 6ther.

REFERENCES 1. HUDON, F.; JACQ~S, A.; & BoIvaN, P. A. Fluothane-Ether: An Azeotropic Mixture. Canad. Anaesth. Soc. J. 5:403 (1958). 2. PORTEa, R. (ed.) Gas Chromatography in Biology and Medicine. London: Churchill ( 1969 ). 3. DAvms, J. I.; BAKERMAN,S.; GIsrI, G. B.; ANGELL, S. N.; & FREDEI',ICKSON,E.L. Deter- ruination of Halothane-Ether Ratios by Infrared Spectrometry. . 28:143 (1962). 4. Ha.rJ., K. C.; NoRms, F.; & DOWNS, S. Physical Chemistry of Halothane-Ether Mixtures. Anesthesiology. 21: 522 (1960). 5. YAMArcrtraA, H.; WAm~svci, B.; SArO, S.; & T~u~_a3E, Y. Gas Chromatographic Analysis of Inhalation in Whole Blood by an Equilibration Method. Anesthesiology. 27:311 (1966). 6. P~v, E. S. & WmSSBEnC~a, A. (ed.) Technique of Organic Chemistry. Vol. 4. New York: Intersclence ( 1951 ). 7. EB~.aso~, C. M. & A~a'usxo, J. F., Ja. Ether Analgesia: Inspired Concentrations, Flam- mability and Levels in Arterial Blood. Anesthesiology. 19:607 (1958).